Project Summary Chronic sleep disturbance affects 10-20% of the population in the developed world, representing a substantial public health problem. Given the ubiquitous nature of sleep across the animal kingdom, intense investigation is underway into the biological functions of sleep. A primary hypothesis is that sleep facilitates memory consolidation following learning, as sleep restriction or fragmentation impairs memory performance across species. The circuitry coupling sleep and memory remains undefined. Recently, ventral tegmental area (VTA) dopaminergic neurons have been demonstrated to control motivational gating of arousal. These cells are well known players in ?reward and salience? circuitry, and send projections to brain centers critical for memory formation and recall (i.e., hippocampus, amygdala, and prefrontal cortex). How these (or local VTA-GABAergic) neurons contribute to sleep-dependent memory consolidation is unknown. Wake-stabilizing hypocretin (Hcrt) neurons in the lateral hypothalamus send dense projections to the VTA, however, it is unknown how (or if) this circuit contributes to Hcrt-mediated arousal or memory function. This proposal will integrate in vivo optogenetics, calcium imaging, and EEG techniques along with behavioral assays to establish (or refute) a role for these cells in sleep-dependent memory consolidation. fMRI technology will be integrated with optogenetic manipulations and quantitative approaches (dynamic causal modeling) to delineate brain-wide responses to Hcrt stimulation. These findings will establish the Hcrt-to-VTA circuit as a node coupling vigilance states to memory consolidation, with the ultimate goal of providing comprehensive insight into disorders of sleep-wake dynamics and memory dysfunction.